We are examining the major depression (MDD) that occurs during exposure to elevated levels of inflammatory cytokines, and specifically focusing on the MDD that develops during interferon-alpha (IFN-a) therapy (IFN-MDD). Because hepatitis C is very prevalent and the primary treatment is IFN-a-based, IFN-MDD is a common disorder. Because IFN-MDD develops within the few months of IFN-a treatment, it is a tractable condition for prospective study, and may be a good target for preventive intervention if those most vulnerable can be identified. A potential advantage is that a homologous set of behaviors can also be induced in IFN-treated mice. Our preliminary studies (i) support a growing literature that IFN-MDD shares many homologies with other MDD types and (ii) find that the whole genome transcriptome from mononuclear cells may be able to predict who is vulnerable to developing IFN-MDD and who is not. These results have identified the mitogen-associated protein kinase (MAPK) pathway as potentially being associated with this vulnerability. The next step that we propose is to determine mRNA biomarkers for IFN-MDD -- using Affymetrix microarrays to prospectively examine mRNA transcriptomes in humans receiving IFN-a-based therapy. In concert, we also intend to develop an animal platform as a translational approach for verifying molecular biomarker transcription patterns - of potential value for causally testing some of the biomarker pathways found in human IFN-MDD. For this, we propose to examine the mRNA transcriptomes and behaviors of mice treated with a behaviorally active human-mouse consensus IFN-a. The data generated by this 2-year study will guide our systematic next steps, which includes a more targeted and statistically powered investigation of the micro-array-identified pathways. PUBLIC HEALTH RELEVANCE: Delineating vulnerability to major depression is important for designing preventive interventions. We are thus examining non-depressed adult people at high risk for depression - because they are prescribed interferon-alpha (IFN-a) for hepatitis C. We are determining whether differences in various genes predict who gets depressed. To refine an animal model for examining these genes, we are also examining at the same time mice who are treated with IFN-a to examine what genes are turned on during IFN-a treatment.